Fragment Couplings via CO2 Extrusion-Recombination: Expansion of a Classic Bond-Forming Strategy via Metallaphotoredox

Article abstract of DOI:10.1021/jacs.5b08304

In this study we demonstrate that molecular fragments, which can be readily coupled via a simple, in situ RO-C=OR bond-forming reaction, can subsequently undergo metal insertion-decarboxylation-recombination to generate C_sp²-C_sp³ bonds when subjected to metallaphotoredox catalysis. In this embodiment the conversion of a wide variety of mixed anhydrides (formed in situ from carboxylic acids and acyl chlorides) to fragment-coupled ketones is accomplished in good to high yield. A three-step synthesis of the medicinal agent edivoxetine is also described using this new decarboxylation-recombination protocol.

Full text of DOI:10.1021/jacs.5b08304

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Communication
Fragment Couplings via CO2-Extrusion-Recombination: Expansion
of a Classic Bond-Forming Strategy via Metallophotoredox
Chi "Chip" Le, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b08304 • Publication Date (Web): 02 Sep 2015
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Fragment Couplings via CO
2
-Extrusion-Recombination: Expansion of a
Classic Bond-Forming Strategy via Metallophotoredox
Chi “Chip” Le and David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
RECEIVED DATE; E-mail: dmacmill@princeton.edu
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
Abstract: In this study we demonstrate that molecular fragments,
which can be readily coupled via a simple, in situ RO–C=OR
bond forming reaction, can subsequently undergo metal insertion–
Conventional Metal-mediated sp -sp Fragment Coupling (Eq 1)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Fragment 1
Fragment 2
M
X
Transition Metal
decarboxylation–recombination to generate Csp
2
–Csp
3
bonds when
Fragment 1
Fragment 2
M = ZnX, B(OR)2
X = halide
subjected to metallaphotoredox catalysis. In this embodiment the
conversion of a wide variety of mixed anhydrides (formed in situ
from carboxylic acids and acyl chlorides) to fragment-coupled
ketones is accomplished in good to high yield. A three-step
synthesis of the medicinal agent edivoxetine is also described
using this new decarboxylation-recombination protocol.
Tsuji-Saegusa CO -Extrusion-Recombination: Enolate Allylation (Eq 2)
2
O
O
Transition Metal
O
CO2-Extrusion
O
Recombination
Metal-catalyzed intermolecular carbon–carbon bond formation
has long been established as the predominant technology for
General CO -Extrusion-Recombination (CO ExR) Coupling (Eq 3)
2
2
fragment coupling in chemical synthesis.
In particular,
organometallic nucleophiles and organic halide/pseudohalide
electrophiles have become the mainstay coupling partners for the
Fragment 1
Fragment 2
O
CO -Extrusion
2
Fragment 1
Fragment 2
O
transition metal-catalyzed production of hetero C
2
–Csp
3
bonds in
Recombination
sp
1
a highly efficient and selective fashion (Eq 1). Moreover, the
allylation and benzylation of enolates via the decarboxylative
formation of π-allyl systems from β-keto-allyl esters, have long
been established as an important variant of the classic Tsuji–Trost
Metallophotoredox: Anhydrides to Ketones using CO ExR (Eq 4)
2
Ni
Ir
2
A
B
A
B
O
mechanism (Eq 2). Recently, the merger of photoredox and
transition metal catalysis (termed metallaphotoredox catalysis)
has gained momentum as a strategy for unique cross-coupling
O
O
O
3
protocols, mainly due to (i) the capacity to employ naturally
mixed anhydride
fragment-coupled ketone
– CO2
trivial C–O formation
challenging C–C formation
occurring functional groups as traceless activation handles and (ii)
the ability to achieve fragment couplings that readily build
Herein, we present the successful implementation of these ideals
and disclose the first application of this expanded CO ExR
concept towards the production of fragment coupled ketones and
challenging Csp
2
–Csp bonds. In this context, our lab recently
3
disclosed a light-enabled decarboxylative cross-coupling strategy
that employs a diverse range of carboxylic acids in lieu of
2
4
Csp –Csp
2 3 bonds.
organometallic nucleophiles in combination with nickel catalysis.
Design Plan. As shown in Scheme 1, our proposed mechanism
begins with oxidative insertion of Ni complex 3 to acid anhydride
1 (generated in situ from carboxylic acid and acyl chloride
coupling partners) to form the corresponding acyl-carboxylate-Ni
These methodologies utilize abundant and easily accessible
0
starting materials to build a diverse array of Csp
2
–Csp bonds at
3
room temperature while producing CO as a traceless byproduct.
2
II
Recently, we became interested in establishing a heretofore
7
complex
4.
Concurrently,
iridium(III)
photocatalyst
unknown fragment-coupling reaction that employs
a CO2-
Ir[dF(CF )ppy] (dtbbpy)PF (7) [dF(CF )ppy = 2-(2,4-difluoro-
phenyl)-5-(trifluoromethyl)pyridine, dtbbpy = 4,4'-di-tert-butyl-
,2'-bipyridine] is known to undergo photoexcitation in the
presence of visible light to yield the corresponding *Ir complex
. This long-lived excited state (τ = 2.3 μs) possesses a high
oxidizing power (E1/2 [*Ir /Ir ] = +1.21 V vs. SCE in MeCN)
and should rapidly accept an electron from the Ni anhydride-
insertion species 4, thereby inducing oxidative decarboxylation to
forge the corresponding alkyl acyl Ni complex 5. Rapid
reductive elimination should then deliver ketone product 2 and the
extrusion, recombination strategy (CO ExR) that in a general
3
2
6
3
2
sense bears the hall marks of the classic Tsuji allylation reaction.
Specifically, we hoped to demonstrate that two fragments that can
be readily coupled via a simple C–O bond forming step (e.g. in
situ formation of an anhydride, ester, carbamate, etc.) might
2
III
8
8
red
III
II
8
subsequently
undergo
metal
insertion–decarboxylation–
II
recombination under metalla-photoredox conditions to enable the
2 3 3–
production of relatively complex C–C bonds (e.g. Csp –Csp , Csp
III
9
Csp
3
Eq 3). While the strategy of CO -extrusion, recombination
2
has long been established in organometallic catalysis for enolate
I
2
,5
corresponding Ni species 6. Finally, completion of both catalytic
cycles would occur simultaneously via single electron transfer
allylation or benzylation, we hoped this new metallophotoredox
mechanism would provide an expansion in the types of organic
fragments or motifs (e.g. nucleophiles and electrophiles) that can
II
red
III
II
(
=
SET) between the highly reducing Ir complex 9 (E
[Ir /Ir ]
1/2
8
I
–1.37 V vs. SCE in MeCN) and the transient Ni species 6 to
be linked via a simple RO–C=OR bond forming step prior to
0
6
reconstitute the ground state of photocatalyst 7 and Ni catalyst 3
(E1/2 [Ni /Ni ] = –1.20 V vs. SCE in DMF).
Studies toward the proposed CO ExR of mixed anhydrides
began with the coupling of hydrocinnamoyl chloride and Boc-L-
CO ExR. As an initial proof of concept, we chose to examine a
2
red
II
0
10
protocol that would selectively combine and convert acid
chlorides and carboxylic acids to fragment-coupled ketones via
the intermediacy of a mixed anhydride (formed in situ, Eq 4).
2
1
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a
Scheme 1. Mechanism of CO
2
-Extrusion-Recombination
2
Table 1. Optimization of Anhydride CO -Extrusion-Recombination
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CO
2
MeO
OMe
O
Extrusion
Me
N
Me
N
N
N
O
O
Boc
O
Boc
Recombination
Boc
O
Boc
N
N
N
N
amino acid anhydride 1
(±)-α-amino ketone 2
byproduct (10)
2,2'-bipyridyl (11)
4,4'−dOMe-2,2'-bpy (12)
Ni0L
n
NiIL
O
C H Ph
2
4
Ir
Ni
2 4
C H Ph
n
N
3
N
6
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Boc
Boc
O
base, MeCN, 25 °C
NiCl2•ligand, 16 h
e−
anhydride (formed in situ)
(±)−CO ExR ketone
2
ligand byproduct 10b ketone
entry
conditions
base
visible light
source
IrIII (7)
1
2
3
4
5
6
7
8c
as shown
as shown
Cs CO
11
11
12
12
−
20%
14%
3%
40%
70%
84%
0%
2
3
Boc
DBU
DBU
DBU
DBU
−
N
IrII (9)
NiIII Ln
as shown
Me
no photocatalyst
no Ni catalyst
no base
0%
O
Boc
IrIII (8)
*
0%
0%
N
O
O
5
12
12
12
0%
0%
NiII Ln
no light
DBU
DBU
0%
0%
e−
Me
as shown
5%
73%
4
O
CO2
a
2
Reactions performed using photocatalyst 7 (1 mol%), NiCl Ÿglyme (5
mol%), bipyridine ligand (5 mol%), hydrocinnamoyl chloride (0.10
mmol), N-Boc-L-proline (0.13 mmol), and base (0.13 mmol). Yields
determined by GC analysis using an internal standard. Major byproduct.
pre-oxidation
complex
traceless
byproduct
b
c
proline in the presence of photocatalyst 7, NiCl Ÿglyme, 2,2'-
bipyridyl (11), Cs CO , and blue LEDs as the light source (Table
). As a critical design element, we recognized that in situ
formation of the requisite anhydride would eliminate the need for
an intermediate isolation step, thereby rendering the overall
transformation operationally simple. To our delight, our initial
experiment furnished the desired fragment-coupled ketone in a
promising 40% yield (Table 1, entry 1) albeit with 20% yield of
Anhydride was synthesized and isolated prior to reaction.
2
2
3
moieties, deliver appreciable levels of efficiency (26 and 27, 50
and 32% yield). Finally, CO ExR provides a new strategy for the
production of aryl substituted ketones as exemplified by the
1
2
formation of adduct 28 in good yield.
We next examined the generality of anhydride CO ExR with
2
respect to the carboxylic acid component. Given their widespread
availability, abundance, and diverse structural complexity, we
were delighted to find that α-amino acids were exemplary
substrates for this new decarboxylation fragment coupling
protocol (Table 2). For example, various 5-membered ring amino
undesired homodimeric ketone 10.
We recognized that
production of this latter symmetrical dialkyl ketone likely arises
from anhydride metathesis (metal or base catalyzed) prior to the
oxidative decarboxylation step. Indeed, variation of the reaction
base from Cs CO to DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
provided a significant increase in the yield of the desired ketone
entry 2, 70% yield). Moreover, we were pleased to find that
implementation of a more electron-donating ligand 12 on the
Ni Cl •Ln complex afforded the desired fragment-coupled ketone
in 84% yield while limiting the formation of symmetrical ketone
0 to less than 3% yield (entry 3). The necessity of each catalytic
component was demonstrated via a series of control experiments
entries 4–7, 0% yield). Finally, the direct implementation of
purified anhydride gave comparable results (entry 8, 73% yield),
demonstrating that the in situ O–C=O formation step does not
impact the efficiency of the subsequent C–C fragment coupling.
With the optimized conditions in hand, we began to explore
the scope of this transformation with respect to the acyl chloride
acids rapidly undergo CO -extrusion-recombination with
2
2
3
hydrocinnamoyl chloride to form the corresponding of α-amino
ketone adducts in good to excellent yield (29–31, 70–82% yield).
Interestingly, the bridged bicyclic ketone 29 was formed as a
single diastereomer while maintaining good levels of reaction
efficiency (70% yield). For amino acid systems beyond proline
(
II
2
derivatives, we found that the photocatalyst Ir[dF(OMe)ppy]2
1
(
(
dtbbpy)PF6 (13) [dF(OMe)ppy
= 2-(2,4-difluorophenyl)-5-
methoxy)pyridine] was more effective (products 32–40). As an
example of the useful levels of complexity that can be generated
in this new CO ExR protocol, direct access to 6- and 7-membered
(
2
cyclic α-amino ketones is readily accomplished (32 and 33, 76
and 69% yield). We were also pleased to find that smaller
strained rings, such as azetidine 34, can be tolerated, albeit in
slightly diminished yield (40% yield). Gratifyingly, this
transformation does not appear to be overly influenced by the
steric constraints of the amino acid substrate (e.g., valine and tert-
leucine systems are readily employed, 35–38, 55–64% yield).
Indeed, N-alkylated N-Boc acids were found to exhibit superior
efficiency over N–H-bearing substrates (cf. 38, 39, and 40). We
speculate that the presence of additional electron-donating groups
on the nitrogen group might lower the barrier to SET in the
oxidative decarboxylation step, resulting in improved rates of
formation of the requisite Ni(III) species (i.e. 5, Scheme 1).
Beyond amino acids, we were pleased to find that α-oxy and ali-
component. As shown in Table 2, CO ExR is successful with a
2
range of α-methylene bearing acid chlorides (14–18, 77–86%
yield). Moreover, various carbo- and heterocyclic substituted
anhydrides may be employed to rapidly generate ketones that
incorporate 3- through 6-membered rings at the α-carbonyl
position (19–25, 65–85% yield). Notably, many of these ketones
would not be readily accessible using conventional ketone
forming technologies such as Weinreb amide-Grignard
1
1,12
additions.
We have found that acid chlorides that contain
sterically demanding groups, such as tert-butyl or neopentyl
2
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Table 2. Mixed Anhydride CO
2
-Extrusion-Recombination: Scope of Acyl Chloride and Carboxylic Acid Components
1
2
3
4
5
6
7
8
9
5 mol% ligand 12
Cl
R
DBU
5 mol% NiCl2•glyme
OH
O
R
R
X
X
X
1 mol% photocat. 7 or 13
O
O
O
O
34 W blue LED, 36h, 25 °C
O
carboxylic acid
acyl chloride
anhydride (formed in situ)
(±)-coupled ketone
acyl chloride scope with N-Boc-L-prolinea
amino acid scope with hydrocinnamoyl chloridec
O
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
C2H4Ph
Ph
C2H4Ph
C2H4Ph
N
N
OMe
N
N
H
N
N
3
Boc
O
Boc
O
Boc
O
Boc
Boc
O
Boc
O
a
a
(±)-31, 80% yielda
(
±)-14, 86% yield
(±)-15, 77% yield
(±)-16, 83% yield
29, 70% yield (>20:1 dr) 30, 82% yield (8:1 dr)
C2H4Ph
N
C2H4Ph
C2H4Ph
N
N
N
N
N
3
O
Boc
O
Boc
O
Boc
O
Boc
O
Boc
O
Boc
(
±)-17, 86% yield
(±)-18, 83% yield
(±)-19, 71% yield
(±)-32, 76% yield
(±)-33, 69% yield
(±)-34, 40% yield
Ph
Cy
t-Bu
H
C2H4Ph
H
C2H4Ph
H
C2H4Ph
N
N
N
N
N
N
Boc
O
Boc
O
Boc
O
Boc
O
Boc
O
Boc
O
(±)-20, 85% yield
(±)-21, 79% yield
(±)-22, 82% yield
(±)-35, 55% yield
(±)-36, 58% yield
(±)-37, 59% yield
Me
Me
Me
Me
O
Me
H
C2H4Ph
Me
C2H4Ph
Bn
C2H4Ph
N
N
O
N
N
N
N
N
Boc
O
Boc
O
Boc
O
Boc
Boc
O
Boc
O
Boc
O
(±)-25, 70% yieldb
(±)-38, 64% yield
(±)-39, 75% yield
(±)-40, 80% yield
(
±)-23, 78% yield
(±)-24, 65% yield
other compatible dialkyl substrates
OMe
Me
Me
Me
Me
Ph
n-C5H11
n-C5H11
N
N
Me
N
O
Boc
O
Me
Boc
O
Boc
O
O
O
O
(±)-41, 65% yieldb
42, 46% yieldb,d
43, 49% yieldb,d
(
±)-26, 50% yield
(±)-27, 32% yield
(±)-28, 72% yield
a
Reactions performed using photocatalyst 7 (1 mol%) in acetonitrile, NiCl
proline (0.13 mmol), and DBU (0.13 mmol). Yield of isolated product. See Supporting Information for experimental procedure. Reactions performed using
photocatalyst 13 (1 mol%) in dioxane using hydrocinnamoyl chloride (0.10 mmol), amino acid (0.10 mmol), and DBU (0.13 mmol). Yield of isolated
2
Ÿglyme (5 mol%), ligand 12 (5 mol%), acyl chloride (0.10 mmol), N-Boc-L-
c
b
d
product. GC yield.
phatic acids can be utilized in this new coupling protocol to forge
the corresponding ketones in moderate to good yield (41–43, 46–
to 4) is likely reversible and non-regioselective (outside of small
electronic and steric perturbations), we presume that the relative
activation barriers of the two possible decarboxylation steps most
likely dictate the observed 85:15 ratio of isotopically labeled
products. This would seem reasonable given that proline
carboxylate undergoes oxidation-decarboxylation much faster
than the corresponding hydrocinnamate, due to the relative
stabilities of the resulting radical intermediates.
presume that cyclopropyl ring opened product 47 must arise from
a Ni -mediated decarbonylation-recarbonylation process, wherein
formation of Ni(II) complex 49 enables cyclopropyl ring opening
13,14
6
5% yield).
During the examination of the substrate scope, an interesting
rearrangement was observed when β-cyclopropyl anhydride 44
formed in situ) was subjected to this decarboxylation-
recombination strategy. As shown in Eq 4, the product obtained
was not the expected β-cyclopropyl ketone (formed in <3% as
determined by H NMR and GC analysis), but instead homoallylic
ketone 45 (formed in 82% yield). Control experiments have
demonstrated that this rearrangement occurs during the CO ExR
pathway (see Supporting Information). Moreover, labeling
experiments involving C-labeled amino acids have shown that
CO loss occurs mainly from the proline subunit with 85% of the
acid chloride carbonyl being retained in the ketone product (Eqs 5
6). Given that the Ni(0) anhydride insertion step (Scheme 1, 3
(
1
6
As such, we
1
II
2
1
7
prior to recarbonylation.
Given the wealth of previously
1
3
reported Ni-catalyzed carbonylation and decarbonylation
1
8,19
reactions,
we feel this mechanism best supports the results of
2
our labeling experiments shown below.
1
5
&
3
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Rearrangement of Cyclopropylacetic Anhydride Substrate (Eq 5)
References.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH:Weinheim, 2004. (b) Seechurn, C. C. C.
J.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed.
Ni
Ir
O
N
N
2
012, 51, 5062.
(2) (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21, 3199.
b) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am. Chem.
Boc
O
O
Boc
O
(
Soc. 1980, 102, 6381. (c) For a review on decarboxylative allylation and
benzylation, see: Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A.
Chem. Rev. 2011, 111, 1846. (d) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz,
B. M. Acc. Chem. Res. 2015, 48, 740.
44,
= 13C
= 12
C
45, 82% yield, 85% 12
C
(
3) (a) Osawa, M.; Nagai H.; Akita, M. Dalton Trans. 2007, 827. (b)
Kalyani, D.; McMurtrey, K. B.; Neufeldt, S. R.; Sanford, M. S. J. Am.
Chem. Soc. 2011, 133, 18566. (c) Ye, Y.; Sanford, M. S. J. Am. Chem.
Soc. 2012, 134, 9034. (d) Rueping, M.; Koenigs, R. M.; Poscharny, K.;
Fabry, D. C.; Leonori, D.; Vila, C. Chem. Eur. J. 2012, 18, 5170. (e)
Sahoo, B.; Hopkinson, M. N.; Glorius, F. J. Am. Chem. Soc. 2013, 135,
Extrusion Recombination with 13C-labeled Mixed Anhydride (Eq 6)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ni
Ir
O
Ph
Ph
N
N
5
505. (f) Fabry, D. C.; Zoller, J.; Raja, S.; Rueping, M. Angew. Chem.
Boc
O
O
Boc
O
Int. Ed. 2014, 53, 10228. (g) Shu, X.; Zhang, M.; He, Y.; Frei, H.; Toste,
F. D. J. Am. Chem. Soc. 2014, 136, 5844. (h) Zoller, J.; Fabry, D. C.;
Ronge, M. A.; Rueping, M. Angew. Chem. Int. Ed. 2014, 53, 13264. (i)
Tellis, J. C.; Primer, D. N.; Molander, G. A. Science 2014, 345, 433. (j)
Lang, S. B.; O’Nele, K. M.; Tunge, J. A. J. Am. Chem. Soc. 2014, 136,
= 13C
= 12
47, 86% yield, 85% 12
C
4
6,
C
1
3606. (k) Yoo, W.-J.; Tsukamoto, T.; Kobayashi, S. Angew. Chem. Int.
Proposed Mechanism Based on Cyclopropyl 13C-labeling Studies (Eq 7)
Ed. 2015, 54, 6587.
(
(
4) (a) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.;
MacMillan, D. W. C. Science 2014, 345, 437. (b) Noble, A.; McCarver,
S. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 624.
5) (a) Jana, R.; Trivedi, R.; Tunge, J. A. Org. Lett. 2009, 11, 3434. (b)
Rodríguez, N.; Manjolinho, F.; Grünberg, M. F.; Gooβen, L. J. Chem.
Eur. J. 2011, 17, 13688. (c) Hossian, A.; Singha, S.; Jana, R. Org. Lett.
O
O
O
O
N
Ni
L2
N
Ni
L2
O
48
Boc
O
51
50
Boc
2
014, 16, 3934. (d) Pfister, K. F.; Grünberg, M. F.; Gooβen, L. J. Adv.
Synth. Catal. 2014, 356, 3302.
decarbonylation
carbonylation
(6) Example of in situ generation of allyl ester for decarboxylative allylation
of arylglyoxylic acid was reported by Gooβen and coworkers: Grünberg,
M. F.; Gooβen, L. J. J. Organomet. Chem. 2013, 744, 140.
(7) (a) Uhlig, E.; Bernd, N. Z. Chem. 1981, 21, 451. (b) Fischer, R.; Walther,
D.; Kempe, R.; Sieler, J.; Schonecker, B. J. Organomet. Chem. 1993,
447, 131. (c) Kajita, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2008, 130, 17226. (d) Ochi, Y.; Kurahashi, T.; Matsubara, S. Org. Lett.
ring
4
9
opening
O
O
N
NiL2
CO
N
NiL2
Boc
O
Boc
O
CO
2
011, 13, 1374. (e) Zhao, C.; Jia, X.; Wang, X.; Gong, H. J. Am. Chem.
Soc. 2014, 136, 17645.
Finally, we have applied our CO ExR technology to a three-
step synthesis of (±)-edivoxetineŸHCl,
(8) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R. A. Jr.;
Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17, 5712.
(9) Either oxidation of nickel-carboxylate complex or free carboxylate are
operable. See SI for details.
2
a medicinal agent
2
0
indevelopment for the treatment of ADHD. As shown,
commercial acid 52 and acyl chloride 53 were readily coupled
using the optimized metallaphotoredox conditions to generate
ketone 54 in good yield (68%). The synthesis was thereafter
completed via a Grignard addition, followed by HCl-mediated
Boc removal to afford (±)-edivoxetineŸHCl in 55% yield over
three steps.
(
10) Durandetti, M.; Devaud, M.; Perichon, J. New J. Chem. 1996, 20, 659.
(11) Selected examples: (a) Gao, X.; Liu, Y.; Kwong, S.; Xu, Z.; Ye, T. Org.
Lett. 2010, 12, 3018. (b) Ma, N.; Yao, Y.; Zhao, B.-X.; Wang, Y.; Ye,
W.-C.; Jiang, S. Chem. Commun. 2014, 50, 9284.
(
12) Dieter, R. K.; Sharma, R. R.; Yu, H.; Gore, V. K. Tetrahedron 2003, 59,
1
083.
(13) Early examples of formation of symmetrical ketones from corresponding
anhydrides: (a) Easterfield, T. H.; Taylor, C. M. J. Chem. Soc. 1911, 99,
2
298. (b) Grün, A.; Ulbrich, E.; Krczil, F. Angew. Chem. 1926, 39, 421.
(c) Man, E. H.; Hauser, C. R. J. Am. Chem. Soc. 1950, 72, 3294.
14) Substrates with slow oxidative decarboxylation results in competitive
anhydride metathesis, which leads to formation of homo-coupling
adducts. Extensive studies are ongoing to suppress such pathway for
(
Three-step Synthesis of (±)-Edivoxetine•HCl via a CO ExR Strategy
2
O
O
O
unsymmetrical aliphatic anhydride substrates.
12
O
Ni
Ir
O
(15) With inverse isotopic labeling of 44 (carboxylate = C, hydrocinnamyl
OH Cl
1
3
1
3
1
2
chloride = C) we observed an 85:15 ratio of C: C ketone product.
16) (a) Bockman, T. M.; Hubig, S. M.; Kochi, J. K. J. Am. Chem. Soc. 1996,
118, 4502. (b) Bockman, T. M.; Hubig, S. M.; Kochi, J. K. J. Org. Chem.
1997, 62, 2210.
(
(
O
O
N
N
5
2
53
Boc
Boc
17) Rearrangement can occur via different mechanisms. (a) Pinke, P.A.;
Stauffer, R. D.; Miller, R. G. J. Am. Chem. Soc. 1974, 96, 4229. (b)
Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal. 2002, 344, 111. (c)
Masarwa, A.; Marek, I. Chem. Eur. J. 2010, 16, 9712. (d) Newcomb, M.,
Kinetics of Radical Reactions: Radical Clocks. In Radicals in Organic
Synthesis, 1st ed.; Renaud. P. Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; Vol. 1, pp 317. (e) Biswas, S.; Weix, D. J. J. Am. Chem. Soc. 2013,
135, 16192.
18) Examples of decarbonylation in nickel complexes: (a) Otsuka, S.;
Nakamura, A.; Yoshida, T.; Naruto, M.; Ataka, K. J. Am. Chem. Soc.
1973, 95, 3180. (b) Yamamoto, T.; Ishizu, J.; Kohara, T.; Komiya, S.;
Yamamoto, A. J. Am. Chem. Soc. 1980, 102, 3758. (c) Ansis, M.;
Sanford, M. S. Organometallics 2014, 33, 3831.
(
±)-54, 68% yield
O
F
F
OH
H
O
MgBr
(
OMe
N
H•HCl
1)
OMe
2
) 4 M HCl in dioxane
(±)-edivoxetine•HCl
55% yield overall
(19) Examples of carbonylation in nickel complexes: (a) Bauld, N. L.
Tetrahedron Lett. 1963, 4, 1841. (b) Chiusoli, G. P.; Cassar, L. Angew.
Chem. Int. Ed. 1967, 6, 124. (c) Ocafrain, M.; Devaud, M.; Troupel, M.;
Perichon, J. J. Chem. Soc., Chem. Commun. 1995, 2331. (d) Dolhem, E.;
Barhdadi, R.; Folest, J.; Nédelec, J. Y.; Troupel, M. Tetrahedron 2001,
57, 525. (e) Wotal, A. C.; Ribson, R. D.; Weix, D. J. Organometallics
8
1% yield, 17:1 dr
Acknowledgement.
Financial support was provided by
NIHGMS (R01 GM078201-05) and gifts from Merck and Amgen.
2
014, 33, 5874. (f) Hoshimoto, Y.; Ohata, T.; Sasaoka, Y.; Ohashi, M.;
Ogoshi, S. J. Am. Chem. Soc. 2014, 136, 15877.
Supporting Information Available. Experimental procedures,
structural proofs, and spectral data for all new compounds are
provided (PDF).
(20) Campell, G. I.; Cases-Thomas, M. J.; Man, T.; Masters, J. J.; Eugenine
Rudyk, H. C.; Walter, M. W. U.S. Patent Appl. 2007/0083046 A1, 2007.
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